SK282623B6 - Use of cyclodextrin and mucoadhesive emulsion - Google Patents

Abstract

Use of cyclodextrin or derivative thereof as mucoadhesive in an emulsion or in aqueous solution, whilst cyclodextrin or derivative thereof is used in the amount in the scope from 10 to 70 wt. %, related to the total weight of the preparation. Mucoadhesive emulsion, which contains itraconazole and cyclodextrin or derivative thereof in the amount in the scope from 10 to 70 wt. % related to the total weight of the preparation.

Description

Technical field

The invention relates to the use of a cyclodextrin and a mucoadhesive emulsion.

BACKGROUND OF THE INVENTION

Effective vaginal administration devices that are well handled require sufficient adhesion to the vaginal mucosa to prevent the product from shedding out of the vagina. Thus, the vaginal compositions should preferably have suitable mucoadhesive properties. The gels, foams, creams, suppositories and tablets that are currently used in the treatment of vaginal diseases, disintegrate very rapidly when inserted into the vaginal cavity and have insufficient adhesion to the vaginal walls. Therefore, upon administration of such compositions, an unpleasant leakage of the composition occurs, thereby also reducing the effectiveness of the composition. It is an object of the present invention to solve this problem by developing a suitable mucoadhesive emulsion.

SUMMARY OF THE INVENTION

The invention is based on the use of cyclodextrin or a derivative thereof as a mucoadhesive in an emulsion or aqueous solution. The cyclodextrin or derivative thereof is used in an amount of 10 to 70% by weight, based on the total weight of the composition. The mucoadhesive compositions of the invention may be applied to various mucous membranes, such as the mucous membranes of the nose, mouth, and especially the vaginal mucosa. The compositions of the invention preferably contain a drug, such as an antibacterial, antiviral drug or contraceptive. Most often, the compositions of the invention will contain an antifungal agent. Examples of antifungal agents that can be incorporated into the compositions of the invention include, for example, miconazole, clotrimazole, ketoconazole, terconazole, econazole, butoconazole, fluconazole, and preferably itraconazole.

Another aspect of the present invention are mucoadhesive emulsions comprising an amount of itraconazole and cyclodextrin or a derivative thereof in an amount ranging from 10 to 70% by weight based on the total weight of the composition. The compositions of the invention may optionally contain other components with mucoadhesive properties in addition to cyclodextrin.

Itraconazole is a broad-spectrum antifungal compound that has been published in US 4,267,179. In addition to the advantageous mucoadhesive properties, itraconazole-based compositions of the invention have the additional advantage that they cure the vaginal disease more quickly and less often recur after cure commercially available antifungal agents. In addition, itraconazole compositions have excellent physical chemical stability.

Itraconazole is a generic term for 4- [4- [4- [4 - [[2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3] dioxolan-4-yl] methoxy] phenyl) piperazinyl] phenyl] -2,4-dihydro-2- (l-methylpropyl) -3H-l, 2,4-triazol-3-one. The term "itraconazole" (itraconazole) is used in this specification to refer to the free base, pharmaceutically acceptable salts, stereochemically isomeric forms, and also to the tautomeric form of said compound. A preferred itraconazole compound is the (±) - cis form of the free base. Acid addition salts may be obtained by reacting the free base with suitable acids. Examples of suitable acids include inorganic acids such as hydrohalic acids, i. j. hydrochloric acid, hydrobromic acid and the like, sulfuric acid, nitric acid, phosphoric acid and the like. or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -butenedioic acid, (E) -butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid. ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanamidosulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like. The term "pharmaceutically acceptable acid addition salts" also includes solvates such as hydrates, alcoholates and the like.

Itraconazole addition salts are suitable for increasing the aqueous phase solubility of the active ingredient.

The compositions of the invention comprise cyclodextrin or a derivative thereof. Suitable cyclodextrin derivatives include α-, β- and gamma-cyclodextrin or their ethers and mixed ethers in which one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with a C 1 -C 6 alkyl group, in particular methyl, ethyl or isopropyl; hydroxyalkyl having 1 to 6 carbon atoms, in particular hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl of 1 to 6 carbon atoms in the alkyl radical, in particular carboxymethyl or carboxyethyl of alkylcarbonyl of 1 to 6 carbon atoms in the alkyl radical, in particular acetyl; alkoxycarbonylalkyl or carboxyalkyloxyalkyl, in which all alkyl and alkoxy radicals each contain 1 to 6 carbon atoms, in particular carboxymethoxypropyl or carboxyethoxypropyl; alkylcarbonyloxyalkyl having 1 to 6 carbon atoms in each of the alkyl radicals, in particular 2-acetyloxypropyl. Notable complexing agents and / or solubilizers include, in particular, β-cyclodextrin, 2,6-dimethyl-3-cyclodextrin, 2-hydroxyethyl-3-cyclodextrin, 2-hydroxyethyl-gamma-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, and (2-carboxymethoxy) propyl-3-cyclodextrin, in particular 2-hydroxypropyl-β-cyclodextrin.

The term "mixed ethers" refers to cyclodextrin derivatives in which at least two cyclodextrin hydroxy groups are etherified with different groups such as hydroxypropyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The M.S. can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, the measured values may vary slightly for each cyclodextrin derivative. The M.S. of the cyclodextrin hydroxyalkyl derivatives used in the compositions according to the invention measured by mass spectrometry is in the range from 0.125 to 10, in particular from 0.3 to 3 and in particular from 0.3 to 1.5. A preferred range of M.S. is about 0.3 to about 0.8, and particularly about 0.35 to about 0.5, and most preferably about 0.4. The average molar substitution values determined by NMR or IR are preferably in the range of from 0.3 to 1, in particular from 0.55 to 0.75.

The average degree of substitution (D.S.) refers to the average number of substituted hydroxy groups per anhydroglucose unit. The D.S. value can be determined by various analytical techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, the measured values may vary slightly for each cyclodextrin derivative. In the cyclodextrin derivatives which are suitable for use in the compositions according to the invention, the D S (determined by mass spectroscopy) lies in the range from 0.125 to 3, in particular from 0.2 to 2 or from 0.2 to 1.5. Preferably, the D.S. is in the range of about 0.2 to about 0.7, particularly about 0.35 to about 0.5, and most preferably about 0.4. The values of the average degree of substitution determined by NMR or IR are preferably in the range of

0.3 to 1, in particular from 0.55 to 0.75.

Preferably, the amount of unsubstituted β- or gamma-cyclodextrin is less than 5%, particularly less than 1.5% based on the total cyclodextrin content. Another particularly interesting cyclodextrin derivative is statistically methylated β-cyclodextrin.

Particularly substituted cyclodextrin derivatives, in which the average degree of alkylation of hydroxyl groups at different positions of the anhydroglucose units: about 0 to 20% at the 3-position, about 2 to 70% at the 3-position, about 2 to 70% in position 2 and about 5 to 90% in position 6.

Most preferred of the cyclodextrin derivatives of the present invention are the partially substituted β-cyclodextrin ethers or mixed ethers containing hydroxypropyl, hydroxyethyl and especially 2-hydroxypropyl and / or 2- (1-hydroxypropyl) substituents.

The most preferred cyclodextrin derivative for use in the compositions of the present invention is hydroxypropyl .beta.-cyclodextrin having an M.S. in the range of from 0.35 to 0.50 and containing less than 1.5% unsubstituted .beta.-cyclodextrin. The average molar substitution values determined by NMR or IR are preferably in the range of 0.55 to 0.75.

Substituted cyclodextrins can be prepared by the methods described in US 3,459,731, EP-A 0 149 197, EP-A 0 197 571, US 4,535,152, WO 90/12035 and GB 2,189,245. in the compositions of the invention, as well as information that can be used as a guide in their preparation, purification and analysis, include: "Cyclodextrin Technology", József Szejtli, Kluwer Academic Publishers (1988) chapter Cyclodextrins in Pharmaceuticals; "Cyclodextrin Chemistry", M. L. Bender et al., Springer-Verlag, Berlin (1978); Advances in Carbohydrate Chemistry, Vol. 12 vyd. M. L. Wolfrom, Academic Press, New York (157), Chapter The Schardinger Dextrins, Dexter French p. 189 to 260; 'Cyclodextrins and their Inclusions Complexes', J. Szejtli, Akademiai Kiado, Budapest, Hungary (1982); I. Tabushi, Acc. Chem. Research, 1982, 15, p. 66 to 72; W. Sanger, Angewandte Chemie, 92, p. 343-361 (1981); A.

P. Croft and R. A. Bartsch, Tetrahedron, 39, p. 1417-1474 (1983); Irie et al. Pharmaceutical Research, 5, p. 713-716 (1988); Pita et al. Int. J. Pharm. 29, 73 (1986); DE 3118218; DE 3,317,064; EP-A-94,157; US 4,659,696 and US 4,383,992.

Cyclodextrin and its derivatives are known to increase the solubility and / or stability of pharmaceutical agents. In the case of the itraconazole-based compositions of the present invention, cyclodextrin has a beneficial effect on the solubility of the antifungal agent in the aqueous phase of the composition. It has surprisingly been found that compositions containing more than 10% by weight, based on the total weight of the composition, of cyclodextrin or a derivative thereof, have useful mucoadhesive properties.

The amounts of the individual additives in the emulsions according to the invention are further expressed as a percentage by weight, based on the total weight of the composition. Similarly, the ratios are also by weight.

The concentration of the medicament may in particular be in the range from 0.1 to 20%, preferably from 0.5 to 10%, particularly preferably from 1 to 5%, in particular from 1 to 2% by weight. The amount of cyclodextrin in the compositions of the invention may range from 10 to about 70%, preferably from 25 to 60%, and in particular from 40 to 50% by weight. Drug ratio, i. j. Itraconazole to cyclodextrin may range from about 1: 700 to 1: 2, preferably from 7: 120 to 1: 10, and especially from 1:50 to 1: 25.

The emulsions of the invention consist of an aqueous phase and an oil phase. The compositions of the invention may take the form of an oil-in-water emulsion in which the oil phase is considered to be the internal or dispersed phase while the aqueous phase is considered to be the external or continuous phase. The oil-in-water emulsions of the invention have the advantage that the drug, in particular itraconazole, is dissolved in the aqueous, i.e. external, phase, which is in direct contact with the mucosa. This results in an increase in drug efficacy, which may lead to the possibility of reducing the frequency of drug application per unit time.

Alternatively, the compositions of the invention may take the form of water-in-oil emulsions in which the aqueous phase is considered to be an internal or dispersed phase while the oil phase is considered to be an external or continuous phase. Water-in-oil emulsions have the advantage of having good spreading properties and optimal mucoadhesive properties, so that such compositions are particularly "user friendly". The oily phase of the emulsions preferably comprises a mineral oil, in particular paraffin oil.

The compositions of the invention can be applied in the form of conventional products such as creams, capsules, pessaries, gelatin capsules, coated swabs, vaginal preparations by means of a cannula device operating at manual or mechanical pressure (spray foam) and the like.

In addition to the drug and cyclodextrin, the compositions of the invention will contain various additives such as emulsifiers, buffers, acids or bases, stabilizing agents, thickeners, preservatives and the like.

Suitable emulsifiers include, for example, anionic, cationic, and in particular nonionic emulsifiers, such as sucrose esters, glucose esters, polyoxyethylated aliphatic acid esters, polyoxyethylated aliphatic alcohol ethers, glycerol esters such as glycerol monostearate, sorbitan esters such as sorbitan monopolyate (Span 40 ^(R) ), sorbitan monostearate (Span 60 ^{, R)} , polyoxyethylene sorbitan ester derivatives such as polysorbate 40 (Tween 40 ^(R) ), polysorbate 60 (Tween 60 ^(R) ), cetyldimeticoncopolyol and the like. Preferably, cetyl dimethicone copolyol is used in an amount of from 0.5 to 10%, preferably in an amount of about 2%.

The quenching systems consist of mixtures of suitable amounts of an acid such as phosphoric acid, succinic acid, tartaric acid, lactic acid or citric acid and a base, in particular sodium hydroxide or sodium phosphate. Such buffer systems preferably maintain the pH of the composition in the range of 1 to 4, preferably 2 to 3. Alternatively, the pH of the composition may be adjusted by the addition of an acid such as hydrochloric acid or a base such as sodium hydroxide and the like. Compositions of the invention having a pH of less than 3 are well tolerated by the vaginal mucosa. This is quite surprising in view of the fact that the pH value of prior art vaginal preparations is only slightly acidic (pH about 4). The low pH of the composition of the invention will have a beneficial effect on the antimicrobial properties of the composition.

Suitable stabilizing agents to ensure the physical and chemical stability of the composition of the invention include, for example, inorganic salts such as sodium chloride and the like.

1,2-propanediol, glycerol and the like. Sodium chloride and 1,2-propanediol are preferably used in amounts of 0.5 to 5% each. The preferred amount of sodium chloride is 1% and the amount

The 1,2-propanediol is 3%.

The viscosity of the composition of the invention may be increased by the addition of thickeners, for example, lyophobic agents such as 1-octadecanol, 1-hexadecanol, glycerol monostearate, carbauba wax, beeswax, trihydroxystearate and the like. or lyophilic agents such as cellulose derivatives, for example carboxymethylcellulose, polyethylene glycol, glycol, chitin and derivatives thereof, for example chitosan, poloxamers, clays, natural resins, starch derivatives and the like. The trihydroxystearate is preferably used in an amount of from 0.05 to 5%, particularly preferably in an amount of about 0.5%.

Preferred compositions according to the invention include: itraconazole in an amount of 0.1 to 5%, cyclodextrin in an amount of 10 to 70%, a thickener in an amount of 0.05 to 5%, an emulsifier in an amount of 0, 5 to 10% and a stabilizer in an amount of 0.5 to 10%.

Particularly preferred compositions comprise the following ingredients in the following amounts (percentages are by weight of the total composition):

a) 0.5 to 3% of itraconazole

b) 30 to 70% cyclodextrin

c) 0.1 to 1% thickening agent

d) 1 to 5% emulsifier

e) 1 to 4% stabilizer

f) a buffer, acid or base to maintain the pH of the composition in the range of 1 to 3

(g) 0,5 to 50% of a dermatologically acceptable oil; and

(h) water.

Even more preferred compositions comprise the following ingredients in the following amounts (percentages are by weight based on the total composition):

(a) 1% itraconazole

b) about 43% hydroxypropyl-β-cyclodextrin

c) 0.5% trihydroxystearate

d) 2% cetyldimeticonkopolyol

e) 1% sodium chloride and 3% 1,2-propanediol

f) about 0.4% hydrochloric acid and sufficient sodium hydroxide to maintain the pH of the composition at about 2.7

(g) 20% paraffin oil; and

(h) water.

Other more preferred compositions comprise the following ingredients in the following amounts (percentages are by weight based on the total composition):

(a) 2% itraconazole

b) about 50% hydroxypropyl-β-cyclodextrin

c) 0.5% trihydroxystearate

d) 2% cetyldimeticonkopolyol

e) 1% sodium chloride and 3% 1,2-propanediol

f) about 0.9% hydrochloric acid and sufficient sodium hydroxide to maintain the pH of the formulation at about 2.2

(g) 12,5% paraffin oil; and

(h) water.

In the manufacture of the pharmaceutical compositions of this invention, an effective amount of the drug is mixed homogeneously with cyclodextrin and water, as well as with the oil phase of the emulsion. In a preferred embodiment, the preparation of such compositions comprises the following steps:

1. preparing an aqueous phase containing the drug and cyclodextrin;

(2) acid, base or buffer components are added to the phase of step (1) until the desired pH is reached;

3. prepare the oil phase by stirring at a temperature between 80 and 85 ° C;

4. the phase of step 3 is cooled to a temperature below 40 ° C and emulsifiers are added thereto,

5. with stirring, mix the stage 2 stage with the stage 3 stage.

The compositions thus obtained may optionally be homogenized using techniques well known in the art.

Optionally, the process can be carried out under an atmosphere of an inert gas such as nitrogen or argon that does not contain oxygen. Drugs in micronized forms may be advantageously used. Micronized forms can be prepared by micronization techniques well known in the art, for example, by milling in suitable mills and sieving through suitable sieves.

Another aspect of the invention is the use of defined means for preventing, suppressing or treating mucosal diseases, particularly the vaginal mucosa.

Yet another aspect of the present invention is a method of preventing, controlling or treating mucosal diseases, particularly vaginal infections in warm-blooded animals, particularly humans, comprising administering to the warm-blooded animal a composition defined in an amount effective to prevent, suppress or treat such diseases.

It is contemplated that an effective dose of the composition of the invention will be delivered when the composition is administered once daily for about 1 to 3 days. It will be appreciated that this effective dose may be reduced or increased depending on the response of the subject to be treated and / or depending on the judgment of the attending physician prescribing the composition of the invention. Said dosing therefore serves only as a guide and is not to be construed as limiting the scope of the invention in any way.

The invention is illustrated by the following examples. These examples are illustrative only and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Formulation F1 (cream)

Component Quantity (mg / g)

itraconazole 10 hydrochloric acid p.a. 4.4 hydroxypropyl? -cyclodextrin 436 1,2-propanediol 30 sodium hydroxide q. with. pH 2.7 sodium chloride 10 paraffin oil 200 cetyl dimethicone copolyol 20 trihydroxystearate 5 purified water q. with. ad 1 g

Approach:

1. 10 mg of itraconazole and 4.4 mg of hydrochloric acid are dissolved in 30 mg of 1,2-propanediol with stirring at 35 to 40 ° C;

2. Dissolve 436 mg of hydroxypropyl-β-cyclodextrin in 284.6 mg of purified water with stirring;

3. mix the phases from stages 1 and 2 with stirring;

(4) dissolve 10 mg of sodium chloride under stirring in step (3);

5. add concentrated sodium hydroxide to pH 2.7;

6. with stirring (25 min. ¹ ), 200 mg paraffin oil with 5 mg trihydroxystearate is stirred for 30 minutes at 80-85 ° C;

The 7th phase of Step 6 is cooled to below 40 ° C with stirring, and 20 mg of cetyl dimethicone copolyol are added with stirring;

8. mix the phases from steps 5 and 7 by stirring for 30 minutes.

Similarly, the following are also prepared:

no expulsion of the formulation was observed during the five days of the test animals.

Claims (9)

PATENT REQUIREMENTS Composition F2 (cream) Ingredient Quantity (mg / g) Itraconazole 20 hydrochloric acid p.a. 8,9 hydroxypropyl-β-cyclodextrin 500 1,2-propanediol 30 sodium hydroxide q. with. pH 2.2 sodium chloride 10 paraffin oil 125 cetyl dimethicone copolyol 20 trihydroxystearate 5 purified water q. with. ad 1 g Formulation F3 (cream) Ingredient Quantity (mg / g) Itraconazole 25 hydrochloric acid p.a. 11,1 hydroxypropyl-β-cyclodextrin 530 1,2-propanediol 35 sodium hydroxide q. with. pH 2.0 paraffin oil 45 cetyldimeticoncopolyol 15 trihydroxystearate 5 purified water q. with. ad 1 g Use of a cyclodextrin or derivative thereof as a mucoadhesive in an emulsion or aqueous solution, wherein the cyclodextrin or derivative thereof is used in an amount ranging from 10 to 70% by weight based on the total weight of the composition. The use of claim 1, wherein the amount of cyclodextrin is in the range of 30 to 60% by weight based on the total weight of the composition. The use of claim 1, wherein the composition further comprises a medicament. The use of claim 1, wherein the composition is a vaginal composition. 5. A mucoadhesive emulsion comprising itraconazole and cyclodextrin or a derivative thereof in an amount ranging from 10 to 70% by weight based on the total weight of the composition. 6. Mucoadhesive labeling 7. Mucoadhesive denoting from 1 to 4. 8. The mucoadhesive labeling of intraconazole to cyclodextrin ranges from 1: 700 to 1: 2. emulsion by emulsion according to claim 5, characterized in that it is of the water-in-oil type, according to claim 5, characterized in that its pH lies within the emulsion range by claim 5, characterized in that the weight ratio A mucoadhesive emulsion according to claim 5, characterized in that it comprises: intraconazole in an amount of 0.1 to 5%, cyclodextrin in an amount of 10 to 70%, a thickener in an amount of 0.05 to 5%, an emulsifier in an amount from 0.5 to 10% and a stabilizer in an amount from 0.5 to 10%. End of document Example 2 Six female New Zealand white rabbits were injected intravaginally with an F3 cream of 0.05 g / kg body weight. All animals are examined for clinical signs of impaired health, abnormal behavior or unusual appearance, or the appearance of unusual clinical effects and signs of irritant, toxic and pharmacological response every 4 weeks each day. Conclusions: The tested cream does not affect the clinical appearance and behavior. No leakage of the formulation from the vagina was observed within 4 weeks in any of the test animals. Example 3 Test solution: benzoic acid 2 mg hydroxypropyl-β-cyclodextrin 250 mg concentrated hydrochloric acid q. with. pH 3.04 purified water q. with. ad 1 g Three female albino rabbits were injected intravaginally with 0.25 g of test solution per kg body weight over 5 consecutive days. For none of